INTRODUCTION

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WE HYPOTHESIZED THAT the deletion (D) allele of the angiotensin-converting enzyme (ACE) gene might contribute to elite athletic ability, on the basis of the following tentative evidence: ACE (which converts angiotensin I to angiotensin II) is widely distributed in cell types, including skeletal muscle (10) and, at least in heart muscle, the enzyme level is higher in D homozygotes than in those with ID or II genotypes (3, 11), where I is the insertion allele; and angiotensin II is a growth factor for cardiac myocytes and fibroblasts (12) and vascular smooth muscle cells (4). Furthermore, inheritance of the D allele may relate not only to myocardial infarction (1, 13) but also to processes such as ventricular hypertrophy (15) and restenosis after coronary balloon angioplasty (17), the latter being regarded as a repair process after vascular wall damage. There is also experimental evidence that angiotensin II is involved more generally in tissue repair (18), and overrepresentation of the DD genotype in centenarians (14) suggested to us (16) that augmented tissue repair responses could be involved in this apparent paradox. Such an effect, coupled with effects on cell growth, would be advantageous to the development of elite athletic ability and sustained high-level performance. On the other hand, there is recent evidence that the II genotype might result in a beneficial training effect in army recruits (6).

	METHODS

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The study group of 81 men and 39 women, aged 30 ± 14 (SD) yr, recruited from 1994 to the present, was restricted to those who were, or had been, national (Australian) representatives in highly aerobic sports (hockey, 26; cycling, 25; skiing, 21; track and field, 15; swimming, 13; rowing, 7; gymnastics, 5; other, 8). That is, participants in sports in which a high level of physical performance was not required, such as archery and pistol shooting, or those, such as weight lifting, requiring primarily muscular strength, were not included.

Their results were compared with those of a community control group of healthy subjects, aged 40 ± 6 yr, recruited from the electoral roll (347 men, 338 women). ACE genotyping was carried out as previously described (17).

	RESULTS

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Figure 1 illustrates the distribution of genotypes in the athletes and control subjects and the close agreement between the two groups, in which the genotypes were, respectively, DD, 30 and 29%; ID, 47.5 and 49%; and II, 22.5 and 22%. The odds ratio for athletes to have the DD genotype was 1.06 (95% confidence interval 0.69-1.62) and the II genotype 1.02 (95% confidence interval 0.64-1.62). Allele frequencies in the athlete and control groups were, respectively, D, 54 and 53%; and I, 46 and 47%, the odds ratio for the D allele in athletes being 1.02 (95% confidence interval 0.77-1.34).

View larger version (12K): [in this window] [in a new window]   Fig. 1.   Angiotensin-converting enzyme (ACE) genotype distribution in elite athletes and control subjects, showing close concordance between 2 groups. D, deletion allele; I, insertion allele.

Five of the athletes included in the above analysis were gymnasts, and eight others competed in sports that possibly did not require an excellent level of aerobic fitness. Excluding those from the analysis did not alter the interpretation, the genotypes in the remaining 107 athletes being DD, 34 (32%), ID, 49 (46%), and II, 24 (22.4%); the odds ratio for athletes to have the DD genotype was 1.15 (95% confidence interval 0.74-1.79), and that for the II genotype was 1.01 (95% confidence interval 0.62-1.65). The numbers studied would have detected, with 90% power, a difference of 15% in the frequency of DD and 14% in that of II genotypes between the two groups; that is, for the DD genotype a frequency of 29 plus 15%, or 44%, would have been detected, and, for the II genotype, 36% would have been detected.

The numbers and proportion of female athletes were smaller than those for men and probably too small for valid comparison with the female control group or the athletic men. There were 75 male athletes among the 107 described above: DD, 30 (40%); ID, 29 (39%); II, 16 (21%); the odds ratio of DD for athleticism was 1.50 (95% confidence interval 0.89-2.50) and of II genotype was 0.98 (95% confidence interval 0.54-1.81). Although 8 of 32 female athletes had the II genotype, it is interesting and provocative that only 4 had the DD genotype.

	DISCUSSION

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Montgomery et al. (6) recently reported that the I, rather than the D, allele was significantly associated with the ability of mountaineers to ascend to 7,000 m without oxygen. This particular observation could be related to the specific attribute studied. As reviewed by Cargill and Lipworth (2), the renin-angiotensin system has an important influence on the pulmonary vasculature. It has been subsequently found that exposure to hypoxia increases the expression of ACE in the small pulmonary arteries of the rat and that the pulmonary hypertensive response to hypoxia is reduced by ACE inhibition (7, 8) and specific angiotensin II type 1 receptor inhibition (8, 19). It might be postulated that subjects with the DD genotype have more pulmonary ACE, a more active pulmonary renin-angiotensin system, and greater pulmonary vasoconstriction in response to hypoxia, whereas those with the II genotype are selected for the ability to withstand hypoxia. This hypothesis could be consistent with another recent observation (H. Montgomery, S. Myerson, R. Budget, H. Hemingway, and S. Humphries, personal communication) that the I allele frequency is directly related to the distance over which elite runners compete, suggesting a relationship with some aspect of endurance. However, this proposal is quite contrary to a recent preliminary finding that susceptibility to high-altitude pulmonary hypertension is greater in those with the II genotype (9). That result seems to contradict the finding in mountaineers (6) and was also surprising to the authors, who postulated linkage disequilibrium with some other gene; clearly, the whole question requires further examination, and in larger numbers of subjects.

The finding quoted above on the mountaineers (6) was complemented by a further finding that, after 10 wk of physical training of male army recruits, the ability to perform elbow flexion against resistance was significantly enhanced by inheritance of the I allele (6). However, the results of training of such a community group would not necessarily extrapolate to elite athletic performance, which is likely to depend on complex interactions among musculoskeletal adaptations, cardiovascular and pulmonary variables, tissue repair, and metabolic (5) and psychological factors. Montgomery et al. (5) have subsequently reported that, among the 81 male army recruits studied, those having the II genotype tended to gain total and nonfat mass during training, whereas D carriers tended to lose fat mass, the results being significantly different between these genotypes. This suggests metabolic dependence on ACE genotype, and the implications are unclear but would almost certainly differ among sports.

Our study would have detected an incidence of the II genotype of 40%, which was the incidence of that genotype in the very small group of high-altitude mountaineers (6). However, although we included over 100 athletes, we still did not have sufficient power to detect a smaller, and possibly important, ACE genotype influence on elite athleticism. However, there was no suggestion that the II genotype conferred elite athletic ability and, in men, there was a trend toward the DD genotype. The trend was the opposite in women, but the numbers were too small to draw conclusions. We also had to include athletes involved in a range of sports to obtain sufficient numbers at a truly elite level of physical performance. Our results must, therefore, be regarded as preliminary, but they, and other recent studies (5, 6; H. Montgomery, S. Myerson, R. Budget, H. Hemingway, and S. Humphries, personal communication), emphasize the importance of carrying out very large studies, together with observations on physiological mechanisms, on both male and female athletes involved in various types of sporting activities.